Alimonti, A., Nardella, C., Chen, Z., Clohessy, J. G., Carracedo, A., Trotman, L. C., Cheng, K., Varmeh, S., Kozma, S. C., Thomas, G., Rosivatz, E., Woscholski, R., Cognetti, F., Scher, H. I., Pandolfi, P. P. (March 2010) A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. Journal of Clinical Investigation, 120 (3). pp. 681-693. ISSN 00219738 (ISSN)
Abstract
Irreversible cell growth arrest, a process termed cellular senescence, is emerging as an intrinsic tumor suppressive mechanism. Oncogene-induced senescence is thought to be invariably preceded by hyperproliferation, aberrant replication, and activation of a DNA damage checkpoint response (DDR), rendering therapeutic enhancement of this process unsuitable for cancer treatment. We previously demonstrated in a mouse model of prostate cancer that inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (Pten) elicits a senescence response that opposes tumorigenesis. Here, we show that Pten-loss-induced cellular senescence (PICS) represents a senescence response that is distinct from oncogene-induced senescence and can be targeted for cancer therapy. Using mouse embryonic fibroblasts, we determined that PICS occurs rapidly after Pten inactivation, in the absence of cellular proliferation and DDR. Further, we found that PICS is associated with enhanced p53 translation. Consistent with these data, we showed that in mice p53-stabilizing drugs potentiated PICS and its tumor suppressive potential. Importantly, we demonstrated that pharmacological inhibition of PTEN drives senescence and inhibits tumorigenesis in vivo in a human xenograft model of prostate cancer. Taken together, our data identify a type of cellular senescence that can be triggered in nonproliferating cells in the absence of DNA damage, which we believe will be useful for developing a "pro-senescence" approach for cancer prevention and therapy.
| Item Type: | Paper |
|---|---|
| Additional Information: | PubMed ID: 20197621 |
| Uncontrolled Keywords: | DNA phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase protein p53 animal cell animal experiment animal model article cancer prevention cancer therapy carcinogenesis cell proliferation chromosome inactivation controlled study DNA damage fibroblast human in vivo study mouse mouse embryo nonhuman oncogene priority journal prostate cancer senescence tumor xenograft Animals Cell Aging Cell Line Tumor Disease Models, Animal Embryo Mammalian Fibroblasts Gene Expression Regulation, Neoplastic Humans Male Mice Mice, Knockout Neoplasm Transplantation Prostatic Neoplasms Protein Biosynthesis PTEN Phosphohydrolase Transplantation, Heterologous Tumor Suppressor Protein p53 |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53 diseases & disorders > cancer > cancer types > prostate cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence |
| CSHL Authors: | |
| Communities: | CSHL labs > Trotman lab |
| Depositing User: | CSHL Librarian |
| Date: | March 2010 |
| Date Deposited: | 23 Mar 2012 16:05 |
| Last Modified: | 08 May 2013 16:32 |
| PMCID: | PMC2827955 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/25513 |
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